CN112704671A - Amoxicillin and clavulanate potassium capsule and preparation method thereof - Google Patents

Amoxicillin and clavulanate potassium capsule and preparation method thereof Download PDF

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CN112704671A
CN112704671A CN202011582163.7A CN202011582163A CN112704671A CN 112704671 A CN112704671 A CN 112704671A CN 202011582163 A CN202011582163 A CN 202011582163A CN 112704671 A CN112704671 A CN 112704671A
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amoxicillin
capsule
layer
clavulanate
parts
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CN112704671B (en
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沈勇
李世彩
罗川
王朝胜
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Zhejiang Jutai Pharmaceutical Co ltd
Apeloa Pharmaceutical Co ltd
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Zhejiang Jutai Pharmaceutical Co ltd
Apeloa Pharmaceutical Co ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/424—Oxazoles condensed with heterocyclic ring systems, e.g. clavulanic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4816—Wall or shell material
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
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    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
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    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4891—Coated capsules; Multilayered drug free capsule shells
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
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Abstract

The invention discloses an amoxicillin and clavulanate potassium capsule, which comprises a main material and an auxiliary material which are filled in a hollow capsule made of hydroxypropyl methylcellulose derivatives; the main materials comprise the following components in parts by weight: 120-130 parts of amoxicillin and 31-31.5 parts of potassium clavulanate; the auxiliary materials comprise: 55-65 parts of microcrystalline cellulose, 5-10 parts of silicon dioxide, 5-10 parts of talcum powder and 1-3 parts of magnesium stearate. According to the invention, the amoxicillin and clavulanate potassium compound preparation is prepared into a capsule form, so that the decomposition of active ingredients in the placing process can be effectively avoided, and the drug effect can be maintained for a long time; and the active ingredients in the capsule can be effectively dissolved in the intestinal tract, so that the release consistency of the active ingredients is ensured.

Description

Amoxicillin and clavulanate potassium capsule and preparation method thereof
Technical Field
The invention relates to the field of medicines, in particular to an amoxicillin potassium clavulanate capsule and a preparation method thereof.
Background
Amoxicillin is a broad-spectrum antibiotic, produces bactericidal action by inhibiting the synthesis of bacterial cell walls, and is widely applied to the treatment of respiratory tract, urinary tract, biliary tract infection and typhoid fever caused by sensitive bacteria at present. However, after long-term use, some bacteria develop resistance to amoxicillin because they produce beta-lactamases which can hydrolyze them. The clavulanic acid has weak antibacterial activity, but has strong broad-spectrum beta-lactamase inhibition effect, and can protect beta-lactam antibiotics from being hydrolyzed and inactivated so as to strengthen the antibacterial effect. After the two are prepared into a compound preparation, the amoxicillin is prevented from being damaged by beta-lactamase due to the existence of the clavulanic acid, and the sterilization sensitivity can be effectively kept. The amoxicillin and clavulanate potassium compound preparation enlarges the antibacterial property of amoxicillin, enhances the antibacterial strength of amoxicillin, has the advantages of good curative effect, low side effect incidence and the like, and is a preferred antibiotic for clinically treating moderate and severe infection caused by enzyme-producing resistant bacteria and sensitive bacteria.
The existing amoxicillin and clavulanate potassium compound preparation mainly comprises tablets, granules, suspensions and dispersible tablets. For example, an amoxicillin potassium clavulanate preparation and a preparation method thereof disclosed in the Chinese patent literature, whose publication number is CN110051637A, can prepare amoxicillin potassium clavulanate into two dosage forms, one is to mix amoxicillin and potassium clavulanate with a certain amount of water-soluble matrix, and then prepare into a dropping pill by a dropping pill preparation technology; the other method is that the amoxicillin and the auxiliary materials are firstly subjected to micro-powder pulverization and are uniformly mixed, the potassium clavulanate is dissolved by a certain amount of water and then is used as a bonding agent, and the spraying granulation method is utilized to prepare the granules.
The potassium clavulanate in the preparation formulation is easy to absorb water and decompose after being exposed in the air, so that the drug effect is reduced; in addition, when the preparation is taken, the medicine is in direct contact with the oral cavity, and the mouth feel is not good, so that the taking is difficult.
Disclosure of Invention
The invention aims to overcome the defects that in the existing amoxicillin potassium clavulanate compound preparation, the potassium clavulanate is poor in stability and easy to decompose when meeting water, and the potassium clavulanate in the existing preparation formulation is exposed in the air and is easy to absorb moisture in the air to decompose, so that the drug effect is reduced; in addition, when the existing preparation is taken, the medicine is in direct contact with the oral cavity, the taste is not good, and the problem of difficult taking can be caused, the amoxicillin potassium clavulanate capsule and the preparation method thereof are provided, the amoxicillin potassium clavulanate compound preparation is prepared into the capsule form, the active ingredients can be effectively prevented from being decomposed in the placement process, and the medicine effect can be kept for a long time; and the active ingredients in the capsule can be effectively dissolved in the intestinal tract, so that the release consistency of the active ingredients is ensured.
In order to achieve the purpose, the invention adopts the following technical scheme:
an amoxicillin and clavulanate potassium capsule comprises a main material and an auxiliary material which are filled in a hollow capsule made of hydroxypropyl methylcellulose derivatives; the main materials comprise the following components in parts by weight: 120-130 parts of amoxicillin and 31-31.5 parts of potassium clavulanate; the auxiliary materials comprise: 55-65 parts of microcrystalline cellulose, 5-10 parts of silicon dioxide, 5-10 parts of talcum powder and 1-3 parts of magnesium stearate.
According to the invention, the main materials of amoxicillin and potassium clavulanate are filled in the hollow capsule, so that the potassium clavulanate can be effectively prevented from being absorbed and decomposed in the storage process of the medicine, and the drug effect is reduced; when the medicine is taken, the medicine can not directly contact the oral cavity, so that the taste of the medicine is improved; meanwhile, the main material and the auxiliary material are mixed, and the main material can be smoothly filled into the hollow capsule under the lubricating action of the auxiliary material. In addition, the hollow microcapsule used by the invention is prepared from hydroxypropyl methylcellulose derivatives, so that the defects of strong water absorption and short shelf life of the traditional gelatin hollow capsule are effectively overcome, and the special requirements of specific people such as Islamic and vegetarian people can be met. The active ingredients of the amoxicillin and clavulanate potassium capsule have good release consistency, and all indexes meet the national medicine quality standard.
The hollow capsule comprises an enteric layer and a pre-dissolving layer arranged outside the enteric layer, and the preparation method comprises the following steps:
A) adding the enteric-coated hydroxypropyl methylcellulose derivative into a mixed solvent of acetone and water, stirring for dissolving, standing for defoaming to obtain an inner-layer glue solution;
B) adding the hydroxypropyl methyl cellulose derivative of the pre-dissolved layer into a mixed solvent of acetone and water, stirring for dissolving, standing for defoaming to obtain an outer-layer glue solution;
C) and placing the glue dipping die in the inner glue solution to dip the glue, performing vacuum drying, then placing the glue dipping die in the outer glue solution to dip the glue, performing vacuum drying, and demolding to obtain the hollow capsule.
Preferably, the preparation method of the hydroxypropyl methyl cellulose derivative of the enteric layer and the pre-dissolving layer comprises the following steps: adding hydroxypropyl methyl cellulose and pyridine into acetone, and stirring and dissolving at 65-75 ℃; adding citric acid and 2-octenyl succinic anhydride, reacting at 85-95 ℃ for 6-8 h, and stopping the reaction with deionized water; adding concentrated hydrochloric acid into the reaction solution, stirring for 30-40 min, pouring the obtained product into deionized water, continuously stirring for 20-30 min, standing for 10-12 h, filtering, washing and drying to obtain the hydroxypropyl methylcellulose derivative.
Preferably, the mass ratio of the hydroxypropyl methylcellulose, the citric acid and the 2-octenyl succinic anhydride in the enteric-coated hydroxypropyl methylcellulose derivative is 10: (15-20): (6-8); in the hydroxypropyl methyl cellulose derivative of the pre-dissolving layer, the mass ratio of hydroxypropyl methyl cellulose to citric acid to 2-octenyl succinic anhydride is 10: (10-15): (10-12).
Preferably, the addition ratio of the hydroxypropyl methyl cellulose, the pyridine and the acetone is 10 g: (15-20 mL): (60-80 mL).
Preferably, the wall thickness of the hollow capsule is 0.08-0.15 mm, and the wall thickness of the enteric layer is 0.04-0.1 mm.
Preferably, the mass fraction of the enteric hydroxypropyl methylcellulose derivative or the pre-dissolved hydroxypropyl methylcellulose derivative in the inner layer glue solution and the outer layer glue solution is 20-30%.
Preferably, in the mixed solvent in the steps A) and B), the volume ratio of the propylene alcohol to the water is (8-9): 1.
in the invention, citric acid and 2-octenyl succinic anhydride are used for modifying hydroxypropyl methyl cellulose to prepare hydroxypropyl methyl cellulose derivatives as materials for preparing hollow capsules, and carboxyl is introduced on the hydroxypropyl methyl cellulose through esterification reaction of the hydroxypropyl methyl cellulose with the citric acid and the 2-octenyl succinic anhydride, so that the hydroxypropyl methyl cellulose derivatives prepared by the invention have pH response performance: the carboxyl groups can be ionized at higher pH, and the hydrophilicity is increased, so that the solubility of the hydroxypropyl methyl cellulose derivative is increased; at low pH, however, the carboxyl group is not ionized, the hydrophilicity is reduced, and the solubility of the hydroxypropylmethylcellulose derivative is low. Therefore, the hollow capsule can not be dissolved in gastric juice with lower pH (pH is 1-3) and can be dissolved in intestinal juice with higher pH (pH is 6-7), so that the active ingredients filled in the capsule can be released in the intestinal tract in a positioning way, the bioavailability of the medicine is improved, and the stimulation of the stomach caused by the release of the active ingredients in the stomach is avoided.
When the hydroxypropyl methyl cellulose derivative is prepared, the addition amounts of citric acid and 2-octenyl succinic anhydride have great influence on the response pH and various performances of the product. The addition of citric acid can reduce the response pH of the product, improve the solubility of the product, ensure that the capsule is easy to disintegrate and the dissolution performance of the medicine is good; and the addition of more citric acid can cause poor water resistance and moisture resistance of the capsule, cause the strength reduction of the capsule and prevent the medicine from being stored for a long time. The addition of the 2-octenyl succinic anhydride can improve the response pH of the product, so that the product has good water resistance and strength, and the storage stability of the medicine is improved; however, the solubility of the product is reduced due to the addition of more 2-octenyl succinic anhydride, the capsule is not easy to disintegrate, and the dissolution performance of active ingredients in the medicine is poor. Therefore, accurately controlling the addition amounts of citric acid and 2-octenyl succinic anhydride plays an important role in controlling the properties of the product.
In order to accelerate the dissolution speed of the capsule, thereby shortening the onset time of the medicament and simultaneously prolonging the storage time of the medicament, the invention prepares the hollow capsule into a double-layer form comprising an enteric layer and a pre-dissolved layer, and the enteric layer and the pre-dissolved layer have different strengths and response pH values by adjusting the addition amounts of citric acid and 2-octenyl succinic anhydride in the hydroxypropyl methylcellulose derivatives of the enteric layer and the pre-dissolved layer. The addition amount of citric acid in the outer pre-dissolving layer is high, the addition amount of 2-octenyl succinic anhydride is small, the strength is low, the response pH is 4.2-4.8, and the pre-dissolving layer can be dissolved in duodenum with pH of 4-5; the enteric layer of the inner layer has less citric acid addition amount, more 2-octenyl succinic anhydride addition amount and higher strength, the response pH is 6.3-7.0, and the citric acid can be dissolved in small intestine.
Therefore, the capsule has good strength and moisture resistance through the synergistic effect of the enteric layer and the pre-dissolving layer, is not easy to damage in the storage process, and prolongs the storage time of the capsule. After the capsule is taken, the active ingredients can not be dissolved and released in the stomach, so that the stimulation of the medicine to the stomach is avoided; after entering duodenum, the outer pre-dissolving layer begins to dissolve, so that the capsule wall becomes thin; therefore, the enteric layer of the inner layer can be quickly dissolved after entering the small intestine to release active ingredients, and the onset time of the medicament is effectively shortened.
The invention also discloses a preparation method of the amoxicillin potassium clavulanate capsule, which comprises the following steps:
(1) sieving the main material for later use;
(2) drying the auxiliary materials respectively and sieving for later use;
(3) weighing the main material and the auxiliary material, and uniformly mixing to obtain the filling material;
(4) filling the filling material into a hollow capsule to obtain the amoxicillin and clavulanate potassium capsule.
Preferably, in the step (3), the potassium clavulanate in the main material is weighed and mixed according to 105-107% of the formula amount.
Because the potassium clavulanate as the main component is unstable and is easy to absorb water and degrade, in order to ensure the quality and the curative effect of the product, 105-107% of the potassium clavulanate in the formula is added, so that the content of the potassium clavulanate in the medicine is ensured to meet the standard.
Therefore, the invention has the following beneficial effects:
(1) the amoxicillin and potassium clavulanate main materials are filled in the hollow capsule, so that the potassium clavulanate can be effectively prevented from being absorbed and decomposed in the storage process of the medicine, and the medicine effect is reduced; when the medicine is taken, the medicine can not directly contact the oral cavity, so that the taste of the medicine is improved;
(2) mixing the main material and the auxiliary material, and ensuring that the main material can be smoothly filled into the hollow capsule through the lubricating effect of the auxiliary material;
(3) the hollow microcapsule is prepared from hydroxypropyl methylcellulose derivatives, can be released at fixed points in intestinal tracts, improves the bioavailability of the medicament, avoids the stimulation of the medicament to stomach, and can meet the special requirements of specific groups such as Islamic and vegetarian;
(4) the hollow capsule is prepared into a double-layer form comprising an enteric layer and a pre-dissolved layer, so that the dissolving speed of the capsule is accelerated, and the onset time of the medicament is shortened; and simultaneously, the strength and the moisture resistance of the capsule are improved, and the storage time of the medicine is prolonged.
Detailed Description
The invention is further described with reference to specific embodiments.
Example 1:
an amoxicillin and clavulanate potassium capsule comprises a main material and an auxiliary material which are filled in a hollow capsule. The main materials comprise: 125mg amoxicillin and 31.25mg potassium clavulanate; the auxiliary materials comprise: 60mg microcrystalline cellulose, 8mg silicon dioxide, 8mg talc, 2mg magnesium stearate.
The preparation method of the amoxicillin potassium clavulanate capsule comprises the following steps:
(1) sieving the main materials of amoxicillin and potassium clavulanate by a 40-mesh sieve for later use;
(2) respectively drying microcrystalline cellulose, silicon dioxide, talcum powder and magnesium stearate as auxiliary materials, and sieving with a 40-mesh sieve for later use;
(3) weighing 125.0g of amoxicillin, 33.125g of clavulanate potassium, 60.0g of microcrystalline cellulose, 8.0g of silicon dioxide, 8.0g of talcum powder and 2.0g of magnesium stearate, and uniformly mixing to obtain a filling material;
(4) filling the filling material into a hollow capsule to prepare 1000 amoxicillin and clavulanate potassium capsules.
The hollow capsule comprises an enteric layer with the wall thickness of 0.06mm and a pre-dissolving layer with the wall thickness of 0.04mm, wherein the pre-dissolving layer is arranged outside the enteric layer, and the preparation method comprises the following steps:
A) adding the enteric-coated hydroxypropyl methylcellulose derivative into a mixed solvent of acetone and water (volume ratio of 8:1), stirring for dissolving, standing for defoaming to obtain an inner-layer glue solution with the mass fraction of 25%;
B) adding the hydroxypropyl methyl cellulose derivative of the pre-dissolved layer into a mixed solvent of acetone and water (the volume ratio is 8:1), stirring and dissolving, standing and defoaming to obtain an outer-layer glue solution with the mass fraction of 25%;
C) and placing the glue dipping die in the inner glue solution to dip the glue, performing vacuum drying, then placing the glue dipping die in the outer glue solution to dip the glue, performing vacuum drying, and demolding to obtain the hollow capsule.
The preparation method of the enteric layer and the pre-dissolved layer hydroxypropyl methylcellulose derivative comprises the following steps: adding hydroxypropyl methyl cellulose and pyridine into acetone, wherein the adding ratio of the hydroxypropyl methyl cellulose to the pyridine to the acetone is 10 g: 18mL of: 70mL, stirring and dissolving at 70 ℃; adding citric acid and 2-octenyl succinic anhydride, reacting at 90 deg.C for 7 hr, and stopping reaction with deionized water; and adding concentrated hydrochloric acid into the reaction solution, stirring for 35min, pouring the obtained product into deionized water, continuously stirring for 25min, standing for 11h, filtering, washing and drying to obtain the hydroxypropyl methylcellulose derivative. In the enteric-coated layer hydroxypropyl methyl cellulose derivative, the mass ratio of hydroxypropyl methyl cellulose to citric acid to 2-octenyl succinic anhydride is 10: 18: 7; the mass ratio of hydroxypropyl methyl cellulose, citric acid and 2-octenyl succinic anhydride in the hydroxypropyl methyl cellulose derivative of the pre-dissolving layer is 10: 12: 11.
example 2:
an amoxicillin and clavulanate potassium capsule comprises a main material and an auxiliary material which are filled in a hollow capsule. The main materials comprise: 120mg amoxicillin and 31mg potassium clavulanate; the auxiliary materials comprise: 55mg microcrystalline cellulose, 5mg silicon dioxide, 5mg talc, 1mg magnesium stearate.
The preparation method of the amoxicillin potassium clavulanate capsule comprises the following steps:
(1) sieving the main materials of amoxicillin and potassium clavulanate by a 40-mesh sieve for later use;
(2) respectively drying microcrystalline cellulose, silicon dioxide, talcum powder and magnesium stearate as auxiliary materials, and sieving with a 40-mesh sieve for later use;
(3) weighing 120.0g of amoxicillin, 32.55g of potassium clavulanate, 55.0g of microcrystalline cellulose, 5.0g of silicon dioxide, 5.0g of talcum powder and 1.0g of magnesium stearate, and uniformly mixing to obtain a filling material;
(4) filling the filling material into a hollow capsule to prepare 1000 amoxicillin and clavulanate potassium capsules.
The hollow capsule comprises an enteric layer with the wall thickness of 0.04mm and a pre-dissolving layer with the wall thickness of 0.04mm, wherein the pre-dissolving layer is arranged outside the enteric layer, and the preparation method comprises the following steps:
A) adding the enteric-coated hydroxypropyl methylcellulose derivative into a mixed solvent of acetone and water (volume ratio of 9:1), stirring for dissolving, standing for defoaming to obtain an inner-layer glue solution with the mass fraction of 20%;
B) adding the hydroxypropyl methyl cellulose derivative of the pre-dissolved layer into a mixed solvent of acetone and water (the volume ratio is 9:1), stirring and dissolving, standing and defoaming to obtain an outer-layer glue solution with the mass fraction of 20%;
C) and placing the glue dipping die in the inner glue solution to dip the glue, performing vacuum drying, then placing the glue dipping die in the outer glue solution to dip the glue, performing vacuum drying, and demolding to obtain the hollow capsule.
The preparation method of the enteric layer and the pre-dissolved layer hydroxypropyl methylcellulose derivative comprises the following steps: adding hydroxypropyl methyl cellulose and pyridine into acetone, wherein the adding ratio of the hydroxypropyl methyl cellulose to the pyridine to the acetone is 10 g: 15mL of: 60mL, stirring and dissolving at 65 ℃; adding citric acid and 2-octenyl succinic anhydride, reacting at 85 deg.C for 8 hr, and stopping reaction with deionized water; and adding concentrated hydrochloric acid into the reaction solution, stirring for 30min, pouring the obtained product into deionized water, continuously stirring for 30min, standing for 10h, filtering, washing and drying to obtain the hydroxypropyl methylcellulose derivative. In the enteric-coated layer hydroxypropyl methyl cellulose derivative, the mass ratio of hydroxypropyl methyl cellulose to citric acid to 2-octenyl succinic anhydride is 10: 15: 6; the mass ratio of hydroxypropyl methyl cellulose, citric acid and 2-octenyl succinic anhydride in the hydroxypropyl methyl cellulose derivative of the pre-dissolving layer is 1: 1: 1.
example 3:
an amoxicillin and clavulanate potassium capsule comprises a main material and an auxiliary material which are filled in a hollow capsule. The main materials comprise: 130mg amoxicillin and 31.5mg potassium clavulanate; the auxiliary materials comprise: 65mg microcrystalline cellulose, 10mg silicon dioxide, 10mg talc, 3mg magnesium stearate.
The preparation method of the amoxicillin potassium clavulanate capsule comprises the following steps:
(1) sieving the main materials of amoxicillin and potassium clavulanate by a 40-mesh sieve for later use;
(2) respectively drying microcrystalline cellulose, silicon dioxide, talcum powder and magnesium stearate as auxiliary materials, and sieving with a 40-mesh sieve for later use;
(3) weighing 130.0g of amoxicillin, 33.7g of potassium clavulanate, 65.0g of microcrystalline cellulose, 10.0g of silicon dioxide, 10.0g of talcum powder and 3.0g of magnesium stearate, and uniformly mixing to obtain a filling material;
(4) filling the filling material into a hollow capsule to prepare 1000 amoxicillin and clavulanate potassium capsules.
The hollow capsule comprises an enteric layer with the wall thickness of 0.1mm and a pre-dissolving layer with the wall thickness of 0.05mm, wherein the pre-dissolving layer is arranged outside the enteric layer, and the preparation method comprises the following steps:
A) adding the enteric-coated hydroxypropyl methylcellulose derivative into a mixed solvent of acetone and water (volume ratio of 9:1), stirring for dissolving, standing for defoaming to obtain an inner-layer glue solution with the mass fraction of 30%;
B) adding the hydroxypropyl methyl cellulose derivative of the pre-dissolved layer into a mixed solvent of acetone and water (the volume ratio is 9:1), stirring and dissolving, standing and defoaming to obtain an outer-layer glue solution with the mass fraction of 30%;
C) and placing the glue dipping die in the inner glue solution to dip the glue, performing vacuum drying, then placing the glue dipping die in the outer glue solution to dip the glue, performing vacuum drying, and demolding to obtain the hollow capsule.
The preparation method of the enteric layer and the pre-dissolved layer hydroxypropyl methylcellulose derivative comprises the following steps: adding hydroxypropyl methyl cellulose and pyridine into acetone, wherein the adding ratio of the hydroxypropyl methyl cellulose to the pyridine to the acetone is 10 g: 20mL of: 80mL of the solution is stirred and dissolved at the temperature of 75 ℃; adding citric acid and 2-octenyl succinic anhydride, reacting at 95 ℃ for 6h, and stopping the reaction with deionized water; and adding concentrated hydrochloric acid into the reaction solution, stirring for 40min, pouring the obtained product into deionized water, continuously stirring for 20min, standing for 12h, filtering, washing and drying to obtain the hydroxypropyl methylcellulose derivative. In the enteric-coated layer hydroxypropyl methyl cellulose derivative, the mass ratio of hydroxypropyl methyl cellulose to citric acid to 2-octenyl succinic anhydride is 10: 20: 8; the mass ratio of hydroxypropyl methyl cellulose, citric acid and 2-octenyl succinic anhydride in the hydroxypropyl methyl cellulose derivative of the pre-dissolving layer is 10: 15: 12.
comparative example 1:
an amoxicillin and clavulanate potassium capsule comprises a main material and an auxiliary material which are filled in a hollow capsule. The main materials comprise: 125mg amoxicillin and 31.25mg potassium clavulanate; the auxiliary materials comprise: 60mg microcrystalline cellulose, 8mg silicon dioxide, 8mg talc, 2mg magnesium stearate.
The preparation method of the amoxicillin potassium clavulanate capsule comprises the following steps:
(1) sieving the main materials of amoxicillin and potassium clavulanate by a 40-mesh sieve for later use;
(2) respectively drying microcrystalline cellulose, silicon dioxide, talcum powder and magnesium stearate as auxiliary materials, and sieving with a 40-mesh sieve for later use;
(3) weighing 125.0g of amoxicillin, 33.125g of clavulanate potassium, 60.0g of microcrystalline cellulose, 8.0g of silicon dioxide, 8.0g of talcum powder and 2.0g of magnesium stearate, and uniformly mixing to obtain a filling material;
(4) filling the filling material into a hollow capsule to prepare 1000 amoxicillin and clavulanate potassium capsules.
Wherein the hollow capsule is prepared from enteric layer hydroxypropyl methylcellulose derivative, the wall thickness is 0.1mm, and the preparation method comprises the following steps:
A) adding the enteric-coated hydroxypropyl methylcellulose derivative into a mixed solvent of acetone and water (volume ratio of 8:1), stirring for dissolving, standing for defoaming to obtain an inner-layer glue solution with the mass fraction of 25%;
B) and placing the glue dipping die into the inner layer glue solution for glue dipping, and obtaining the hollow capsule after vacuum drying and demoulding.
The preparation method of the enteric layer hydroxypropyl methyl cellulose derivative comprises the following steps: adding hydroxypropyl methyl cellulose and pyridine into acetone, wherein the adding ratio of the hydroxypropyl methyl cellulose to the pyridine to the acetone is 10 g: 18mL of: 70mL, stirring and dissolving at 70 ℃; and then adding citric acid and 2-octenyl succinic anhydride, wherein the mass ratio of the hydroxypropyl methyl cellulose to the citric acid to the 2-octenyl succinic anhydride is 10: 18: 7, reacting for 7 hours at 90 ℃, and stopping the reaction by using deionized water; and adding concentrated hydrochloric acid into the reaction solution, stirring for 35min, pouring the obtained product into deionized water, continuously stirring for 25min, standing for 11h, filtering, washing and drying to obtain the enteric hypromellose derivative.
Comparative example 2:
an amoxicillin and clavulanate potassium capsule comprises a main material and an auxiliary material which are filled in a hollow capsule. The main materials comprise: 125mg amoxicillin and 31.25mg potassium clavulanate; the auxiliary materials comprise: 60mg microcrystalline cellulose, 8mg silicon dioxide, 8mg talc, 2mg magnesium stearate.
The preparation method of the amoxicillin potassium clavulanate capsule comprises the following steps:
(1) sieving the main materials of amoxicillin and potassium clavulanate by a 40-mesh sieve for later use;
(2) respectively drying microcrystalline cellulose, silicon dioxide, talcum powder and magnesium stearate as auxiliary materials, and sieving with a 40-mesh sieve for later use;
(3) weighing 125.0g of amoxicillin, 33.125g of clavulanate potassium, 60.0g of microcrystalline cellulose, 8.0g of silicon dioxide, 8.0g of talcum powder and 2.0g of magnesium stearate, and uniformly mixing to obtain a filling material;
(4) filling the filling material into a hollow capsule to prepare 1000 amoxicillin and clavulanate potassium capsules.
Wherein the hollow capsule is prepared from a pre-dissolved layer of hydroxypropyl methylcellulose derivative, the wall thickness is 0.1mm, and the preparation method comprises the following steps:
A) adding the hydroxypropyl methyl cellulose derivative of the pre-dissolved layer into a mixed solvent of acetone and water (the volume ratio is 8:1), stirring and dissolving, standing and defoaming to obtain an outer-layer glue solution with the mass fraction of 25%;
B) and placing the glue dipping die into the outer glue solution for glue dipping, and obtaining the hollow capsule after vacuum drying and demoulding.
The preparation method of the hydroxypropyl methyl cellulose derivative of the pre-dissolving layer comprises the following steps: adding hydroxypropyl methyl cellulose and pyridine into acetone, wherein the adding ratio of the hydroxypropyl methyl cellulose to the pyridine to the acetone is 10 g: 18mL of: 70mL, stirring and dissolving at 70 ℃; and then adding citric acid and 2-octenyl succinic anhydride, wherein the mass ratio of the hydroxypropyl methyl cellulose to the citric acid to the 2-octenyl succinic anhydride is 10: 12: 11, reacting for 7 hours at 90 ℃, and stopping the reaction by using deionized water; and adding concentrated hydrochloric acid into the reaction solution, stirring for 35min, pouring the obtained product into deionized water, continuously stirring for 25min, standing for 11h, filtering, washing and drying to obtain the pre-dissolved layer hydroxypropyl methylcellulose derivative.
The amoxicillin and clavulanate potassium capsules prepared in the above examples and comparative examples were tested for quality and the results are shown in table 1.
Table 1: and (3) detecting the quality of the amoxicillin and clavulanate potassium capsule.
Figure BDA0002866136740000081
Figure BDA0002866136740000091
The strength, water content and moisture resistance of the empty capsules prepared in the above examples and comparative examples were measured, and the results are shown in table 2. The moisture resistance test method comprises the following steps: randomly selecting 100 hollow capsules prepared in each example and comparative example, and respectively measuring the total weight of each group; and (3) storing each group of hollow hard capsules in a shady and cool environment with the temperature of 20 ℃ and the relative humidity of 60% for 30 days, then respectively measuring the weight gain value of each group, and dividing by 100 to obtain an average value.
Table 2: and (5) detecting the performance of the hollow capsule.
Item Example 1 Example 2 Example 3 Comparative example 1 Comparative example 2
Tensile Strength (N) 20 16 25 23 13
Water content (%) 7.8％ 7.3％ 8.2％ 7.7％ 8.0％
Weight gain value (mg) of 30d 0.68 0.65 0.71 0.62 2.87
According to the basket-rotating method in pharmacopoeia of the people's republic of China 2015, the amoxicillin potassium clavulanate capsules prepared in the above examples and comparative examples are firstly placed in artificial gastric juice for 2h, then transferred into phosphate buffer with pH 4.2 for 15min, finally transferred into artificial intestinal juice until the capsules are completely dissolved, and the dissolution curves of the main components in the capsules are tested, wherein the results are shown in tables 3 and 4 (the capsules in comparative example 2 are disintegrated in buffer and not transferred into artificial intestinal juice).
Table 3: dissolution results in artificial gastric juice and buffer.
Figure BDA0002866136740000092
Figure BDA0002866136740000101
Table 4: dissolution of main components in the artificial intestinal juice.
Figure BDA0002866136740000102
As can be seen from Table 1, the amoxicillin and clavulanate potassium capsules prepared in the invention meet the regulations in the State food and drug administration Standard YBH 01872014.
As can be seen from tables 2 to 4, the amoxicillin and clavulanate potassium capsules prepared by the method and the raw materials in the invention in the embodiments 1 to 3 have high strength and good moisture resistance, and can be stored for a long time; the capsule is insoluble in gastric juice, active ingredients can not be released in stomach to stimulate stomach, but can be quickly released in intestinal juice, the release amount can reach more than 95% after 20min, and the drug takes effect quickly.
The hollow capsule used in the comparative example 1 is not provided with a pre-dissolving layer, the capsule cannot be dissolved in gastric juice and buffer solution, the release rate in artificial intestinal juice is obviously reduced compared with that in the example 1, the release rate does not reach 95% after 45min, and the drug has slow effect. The empty capsule used in the comparative example 2 is not provided with an enteric layer, so that the drug can be dissolved in the buffer solution and the effect is quick; however, the capsule of comparative example 2 has poor moisture resistance and the storage time of the drug is short.

Claims (10)

1. An amoxicillin and clavulanate potassium capsule is characterized by comprising a main material and an auxiliary material which are filled in a hollow capsule made of hydroxypropyl methylcellulose derivatives; the main materials comprise the following components in parts by weight: 120-130 parts of amoxicillin and 31-31.5 parts of potassium clavulanate; the auxiliary materials comprise: 55-65 parts of microcrystalline cellulose, 5-10 parts of silicon dioxide, 5-10 parts of talcum powder and 1-3 parts of magnesium stearate.
2. The amoxicillin and clavulanate potassium capsule as claimed in claim 1, wherein the hollow capsule comprises an enteric layer and a pre-dissolving layer arranged outside the enteric layer, and the preparation method comprises:
A) adding the enteric-coated hydroxypropyl methylcellulose derivative into a mixed solvent of acetone and water, stirring for dissolving, standing for defoaming to obtain an inner-layer glue solution;
B) adding the hydroxypropyl methyl cellulose derivative of the pre-dissolved layer into a mixed solvent of acetone and water, stirring for dissolving, standing for defoaming to obtain an outer-layer glue solution;
C) and placing the glue dipping die in the inner glue solution to dip the glue, performing vacuum drying, then placing the glue dipping die in the outer glue solution to dip the glue, performing vacuum drying, and demolding to obtain the hollow capsule.
3. The amoxicillin and clavulanate potassium capsule as claimed in claim 2, wherein the preparation method of the hydroxypropyl methylcellulose derivatives of the enteric layer and the pre-dissolved layer is as follows: adding hydroxypropyl methyl cellulose and pyridine into acetone, and stirring and dissolving at 65-75 ℃; adding citric acid and 2-octenyl succinic anhydride, reacting at 85-95 ℃ for 6-8 h, and stopping the reaction with deionized water; adding concentrated hydrochloric acid into the reaction solution, stirring for 30-40 min, pouring the obtained product into deionized water, continuously stirring for 20-30 min, standing for 10-12 h, filtering, washing and drying to obtain the hydroxypropyl methylcellulose derivative.
4. The amoxicillin and clavulanate potassium capsule as claimed in claim 3, wherein the enteric layer hydroxypropyl methylcellulose derivative has a mass ratio of hydroxypropyl methylcellulose, citric acid and 2-octenyl succinic anhydride of 10: (15-20): (6-8); in the hydroxypropyl methyl cellulose derivative of the pre-dissolving layer, the mass ratio of hydroxypropyl methyl cellulose to citric acid to 2-octenyl succinic anhydride is 10: (10-15): (10-12).
5. An amoxicillin and clavulanate potassium capsule according to claim 3 or 4, wherein the addition ratio of hydroxypropyl methylcellulose, pyridine and acetone is 10 g: (15-20 mL): (60-80 mL).
6. The amoxicillin and clavulanate potassium capsule as claimed in claim 2, wherein the wall thickness of the hollow capsule is 0.08-0.15 mm, and the wall thickness of the enteric layer is 0.04-0.1 mm.
7. The amoxicillin and clavulanate potassium capsule as claimed in claim 2, wherein the mass fraction of the enteric layer hydroxypropyl methylcellulose derivative or the pre-dissolved layer hydroxypropyl methylcellulose derivative in the inner layer glue solution and the outer layer glue solution is 20-30%.
8. The amoxicillin and clavulanate potassium capsule as claimed in claim 2 or 7, wherein the volume ratio of the propanol to the water in the mixed solvent of steps A) and B) is (8-9): 1.
9. a process for the preparation of amoxicillin and potassium clavulanate capsules as claimed in any one of claims 1 to 8, characterised by the steps of:
(1) sieving the main material for later use;
(2) drying the auxiliary materials respectively and sieving for later use;
(3) weighing the main material and the auxiliary material, and uniformly mixing to obtain the filling material;
(4) filling the filling material into a hollow capsule to obtain the amoxicillin and clavulanate potassium capsule.
10. The preparation method of amoxicillin and clavulanate potassium capsules as claimed in claim 9, wherein in step (3), the clavulanate potassium in the main material is weighed and mixed according to 105-107% of the formula amount.
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